Bo Angelin & Mats Rudling group

Lipid and bile acid metabolism and atherosclerosis 

Cardiovascular diseases are one of the leading causes of death in our country. Elevated cholesterol levels in the blood is one major risk factor for these diseases. Studies have shown that lowering cholesterol in the blood improves the prognosis of cardiovascular disease and prolongs survival.

Our research aim to understand how blood cholesterol is regulated in man by different hormones and by various components in our diet and by inherited familial factors. How this regulation occurs is one key line of the group's research.

Understanding normal physiology often comes from the understanding of the specific mechanisms behind certain diseases and forms the platform to develop novel therapeutic regimens and diagnostic tools. In our work we conduct in vitro, animal and clinical human studies to find and explore the mechanisms regulating blood lipids in humans.

Keywords: Bile acids, thyroid hormone, PCSK9, fibroblast growth factor 19, 21

Members

Bo Angelin, PhD, MD. Senior professor.

Bo Angelin is Professor of Clinical Metabolic Research at KI and Consultant at the Department of Endocrinology, Metabolism & Diabetes (Head 1993-2011) at Karolinska University Hospital, where he has also served as Director of Research. His research interest is regulation of lipid and cholesterol metabolism with special emphasis on humans, and how this knowledge can be used for development of new forms of diagnostics and treatments.

Mats Rudling, PhD, MD. Professor.

Mats Rudling is Professor in Experimental Cardiovascular Research. His thesis work presented 1986 at the Department of Pharmacology, KI was on LDL receptor expression in tumors.  His main interest has later been regulation of plasma LDL cholesterol in man by hormones such as estrogen, growth hormone, thyroid hormone and glucagon but also the effects of diet. In 1988-90 he did post doc work at the nobel laureates M Brown & JL Goldstein, Dallas, Texas who discovered the LDL receptor. In 1992 he discovered that glucagon stimulates the expression of LDL receptors in vivo by a novel posttranscriptional regulatory mechanism that he in 2009 showed is be due to suppressed expression of PCSK9, a protein that lead to the destruction of the LDL receptor. PCSK9 inhibition is today a most powerful tool to stimulate LDL receptors to reduce LDL levels.  Some current lines of research are now: Role of PCSK9 for the hormonal and dietary regulation of LDL receptors; regulation of bile acid synthesis in man; role of food intake; individual bile acids and linkage to hyperlipidemia and gallstone disease; lipoproteins in interstitial fluid.

Amani Al-Khaifi, MSc. PhD student.

I obtained my Master’s degree in Biomedicine from Karolinska Institutet in 2010. Currently I am working on research projects that aim to understand the mechanisms by which bile acid metabolism is regulated using both human and animal models. We tempted to gain this understanding by manipulating the enterohepatic circulation in healthy subjects using different safe methods. The investigation is also extended to explore the link between bile acids and lipid metabolism.

Amit Laskar, PhD. Postdoc.

I studied Pharmacy in Bangalore, India followed by a Master’s degree in Biomedicine at Linköping University, Sweden. Also my PhD in Medicine was from Linköping University, Sweden, where i focused on understanding the molecular mechanisms including abnormal lipid metabolism underlying pathophysiology of atherosclerosis. I also evaluated cellular effects of anti-oxidants and iron containing MRI contrast agents intended for their possible use in plaque diagnosis. My current focus now is to further understand the discrepancies in lipid metabolism in conjunction with bile acid metabolism and underlying genes in the development of chronic metabolic and inflammatory conditions as Diabetes and Atherosclerosis. 

Christina Savva, MSc. Research assistant.

I recently received my Master’s degree in Nutrition from Stockholm University (2016). For my master thesis project I have investigated the role of estrogen receptor beta activation in the regulation of metabolism in obese female mice. My current research is focused on the in vivo characterization of sex-dependent lipid partitioning in liver and adipose depots in female and male offspring born from lean or obese mothers. We also aim to identify new markers of sex-dependent regulation of lipid composition in liver and serum of female and male mice.

Daniela Strodthoff, PhD. Postdoc

In my current research project I am using different strategies, including the use of both in vivo- and in vitro-models, to characterize the function of gene variants found in families with monogenic dyslipidemia.

I hold a PhD in Medical Science from Karolinska Institutet (Thesis: Role of immune mediators in metabolic syndrome and atherosclerosis; 2014). I also have a Master in Biology (Dipl. biologist) from the Christian-Albrechts-University of Kiel, Germany (2006).

Ingela Arvidsson, MSc. Laboratory manager

Responsible for advanced analytical procedures employed including GC-MS, LC-MS-MS, HPLC, FPLC, and immunohistochemistry. 

Lena Emtestam, Administrator

I am responsible for the administration in the metabolic group. I provide administrative support to students, post graduates and researchers such as help with applications, employment contracts, economy, planning of and coordinating meetings, and additional tasks. 

Lisbet Benthin, Laboratory technician

Marcela González, PhD. Postdoc.

I focus my research on the characterization of the sex-dependent lipid partitioning and composition in liver, skeletal muscle and adipose depots in vivo in obese female and male mice. Our research aims: i) to explore the effect of estrogen receptor activation or deletion, ii) to identify new markers of sex-dependent regulation of lipid composition in liver and serum of female and male mice, and iii) to identify the sex-dependent markers in human serum of obese girls and boys. I hold a PhD in Physiology, Physiopathology and Pharmacology from University of Grenoble, France (Thesis: Molecular system bioenergetics of muscle cells: structure-function relationship in regulation of compartmentalized energy metabolism). I also have a Master in Science degree (MSc) in Biochemical Science from National Autonomous University of Mexio and a baschelor degree in Nutrition and Food Sciences.

Marion Korach-Andre, PhD. Associate professor

I dedicate my research work to human health with a special focus on the role of nutrients in health and disease for more than 15 years. I have been particularly interested on the role of nuclear receptors in the regulation of metabolism homeostasis in obesity and associated metabolic diseases. Recently, I focused my research on the role of sex hormone receptors in lipid metabolism regulation, with a specific interest on the role of estrogen receptors in the sex-dependent response to obesity and metabolic disorders. In humans, sexual dimorphism has been described not only related to body weight control, but also to body composition, fat distribution, and fuel metabolism. We have the aim to elucidate if the sexual dimorphism in obesity is due to a sex-specific regulation of lipid species and genes related to fat partitioning and the role of estrogen in this regulation. In order to develop gender appropriate therapies for treating metabolic disorders,there is a need to  understand the progression of these metabolic diseases in both females and males. 

Moumita Ghosh Laskar (née Ghosh), BSc. PhD student.

I hold a bachelor degree in Pharmacy from West Bengal University of Technology, India and a master degree in Medical Bio-Sciences (Bio-Medicine) from Linköping University, Sweden. I’m currently doing my PhD at Department of Medicine, Karolinska Institutet. My research is focusing on hormonal regulation on lipid and bile acid metabolism. As known, hormones play crucial role in human physiology and imbalance in hormone levels could cause various pathological conditions. Hormones such as estrogen, testosterone and adrenocorticotropic hormone (ACTH) influences cholesterol metabolism. In my studies, I’m investigating the underlying mechanism behind the hormonal effects on cholesterol and bile acid metabolism. My PhD projects include cellular, animal and clinical studies. My work is primarily focused on role of LDL-receptor regulating molecule Proprotein convertase subtilisin/kexin type 9 (PCSK9).

Sara Straniero, PhD. Assistant professor.

My research at the moment is focused on cholesterol metabolism and its connections to dyslipidemia, atherosclerosis and cardiovascular disease (CVD), aiming to understand how blood cholesterol is regulated in diet. I’m collaborating with outstanding scientists in different countries on projects dedicated to the understanding of the biology of PCSK9 and its implication in hypercholesterolemia and CVD. In my work I conduct animal studies on the effect of saturated and polyunsaturated fatty acids enriched diets and caloric restriction on lipid metabolism and on prevention of age-related hypercholesterolemia. My research includes also studies on the regulation of bile acid metabolism in healthy and obese subjects.

Johanna Apro (née Lundberg), PhD. Postdoc.

My research is focusing on investigating the role of interstitial fluid lipoproteins in the development of atherosclerosis. Since interstitial fluid is in close proximity to all cells in the body (e.g. in the vascular wall where atherosclerosis develops), the study of lipoproteins and different biomarkers in this fluid is highly relevant for the understanding of the physiology and pathophysiology of the human body. The main focus so far has been to study interstitial fluid lipoproteins in type 2 diabetes. These patients have an increased risk of developing atherosclerosis that cannot solely be explained by traditional risk factors, which makes them particularly interesting to study. Planned projects include studies of additional patient groups, as well as animal studies for a deeper mechanistic understanding.

I hold a PhD in Medical Science from Karolinska Institutet (Thesis: Studies on cholesterol and lipoprotein metabolism – emphasis on diabetes and sugar; 2015). I also have a Master of Science degree (MSc) with a major in Nutrition from Stockholm University (2009).

Ylva Bonde, PhD. Assistant professor.

I’m strongly committed to research aiming to increase human health and life quality. Currently, my research is focused on the regulation of lipid and bile acid metabolism, with emphasis on the effects of thyroid hormone and thyroid hormone analogs. Lipid metabolism disorders may cause a number of pathological conditions such as atherosclerosis, steatosis, and obesity to which a plethora of comorbidities are associated. In general, many of these are increasing on a global level and comprise a huge challenge for our future health care system. Thus the need for a deeper understanding behind these conditions is pivotal for novel and improved treatment options.

My projects encompass both clinical and animal studies, and include collaborations with established research experts both within Sweden and internationally. Successful collaborations have also been achieved with KaroBio and Eli Lilly & Co. I hold a PhD in Medical Science from Karolinska Institutet (Thesis: Studies on the effects of thyroid hormone on cholesterol and lipoprotein metabolism; 2012). I also have a Master of Science degree (MSc) with a major in Nutrition from Stockholm University (2006).

Alumni

Beatrice Sjöberg

Cecilia Gälman

Lena Beckman (née Persson)

Lilian Larsson

Lisa-Mari Mörk (née Nilsson)

Manuela Matasconi

Paolo Parini

Thomas Lundåsen

Wei Liao

Funding

  • Cardiovascular Program, Karolinska Institutet/Stockholm County Council
  • Diabetesfonden
  • Dutch Heart Foundation
  • Fondation Leducq
  • Foundation of Old Female Servants
  • Grönberg Foundation
  • KaroBio
  • KI fonder
  • Lilly Research Laboratories, Eli Lilly & Co
  • Novo Nordisk Foundation
  • Stockholm County Council (ALF)
  • Swedish Heart-Lung Foundation
  • Swedish Nutrition Foundation
  • Swedish Research Council
  • Swedish Society of Medicine

Publications

Treatment with the natural fxr agonist chenodeoxycholic acid reduces clearance of plasma ldl whilst decreasing circulating pcsk9, lipoprotein(a) and apolipoprotein c-iii. Ghosh Laskar M, Eriksson M, Rudling M, Angelin B. J. Intern. Med. 2017;281:575-585. PMID: 28145001

Influence of physiological changes in endogenous estrogen on circulating pcsk9 and ldl cholesterol. Ghosh M, Galman C, Rudling M, Angelin B. J. Lipid Res. 2014; 56(2):463-469. PMID: 25535288

Cholestyramine treatment of healthy humans rapidly induces transient hypertriglyceridemia when treatment is initiated. Sjöberg BG, Straniero S, Angelin B, Rudling M. Am J Physiol Endocrinol Metab.;313(2):E167-E174, 2017. PMID: 28487440

Acute caloric restriction counteracts hepatic bile acid and cholesterol deficiency in morbid obesity. Straniero S, Rosqvist F, Edholm D, Ahlström H, Kullberg J, Sundbom M, Risérus U, Rudling M. J Intern Med. 281(5):507-517, 2017. PMID: 28261926

Potential role of milk fat globule membrane in modulating plasma lipoproteins, gene expression, and cholesterol metabolism in humans: a randomized study. Rosqvist F, Smedman A, Lindmark-Månsson H, Paulsson M, Petrus P, Straniero S, Rudling M, Dahlman I, Risérus U. Am J Clin Nutr. 102(1):20-30, 2015. PMID: 26016870

Impaired cholesterol efflux capacity of HDL isolated from interstitial fluid in type 2 diabetes. Apro J, Tietge UJF, Dikkers A, Parini P, Angelin B, Rudling M. Arterioscler Thromb Vasc Biol. 2016 May;36(5):787-91. PMID: 27034474

Levels of atherogenic lipoproteins are unexpectedly reduced in interstitial fluid from type 2 diabetes patients. Apro J, Parini P, Broijersén A, Angelin B, Rudling M. J Lipid Res. 2015 Aug;56(8):1633-9. PMID: 26092865

Influence of dietary sugar on cholesterol and bile acid metabolism in the rat: Marked reduction of hepatic Abcg5/8 expression following sucrose ingestion. Apro J, Beckman L, Angelin B, Rudling M. Biochem Biophys Res Commun. 2015 Jun 12;461(4):592-7. PMID: 25912874

Circulating Hepcidin-25 Is Reduced by Endogenous Estrogen in Humans. Lehtihet M, Bonde Y, Beckman L, Berinder K, Hoybye C, Rudling M, Sloan JH, Konrad RJ, Angelin B. PLoS One. 2016 Feb 11;11(2):e0148802. doi: 10.1371/journal.pone.0148802. PMID: 26866603

Mice Abundant in Muricholic Bile Acids Show Resistance to Dietary Induced Steatosis, Weight Gain, and to Impaired Glucose Metabolism. Bonde Y, Eggertsen G, Rudling M. PLoS One. 2016 Jan 29;11(1):e0147772. doi: 10.1371/journal.pone.0147772. PMID: 26824238

Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans. Bonde Y, Breuer O, Lütjohann D, Sjöberg S, Angelin B, Rudling M. J Lipid Res. 2014 Nov;55(11):2408-15. doi: 10.1194/jlr.M051664. PMID: 25172631

Importance of PCSK9 for the hormonal and dietary regulation of rat liver LDL receptors. Persson L, Gälman C, Angelin B, and Rudling M. Endocrinology 2009;150:1140-6. PMID: 19008317

Pronounced variation in bile acid synthesis in man is related to gender, hypertriglyceridemia, and circulating fibroblast growth factor19. Gälman C, Angelin B and Rudling M.  J of Internal Medicine, 2011, 270:580-8. PMID: 22003820

Increased colonic bile acid exposure: A relevant factor for symptoms and treatment in irritable bowel syndrome.  Bajor A, Törnblom, H, Rudling M, Kjell-Arne Ung, K-A, Simrén, M. Gut. 2015, 64:84-92. PMID: 24727487

Specific inhibition of bile acid transport alters plasma lipids and GLP-1. Rudling M, Camilleri M, Graffner H, Holst J.J, Rikner L. BMC Cardiovascular Disorders. 2015 Jul 22;15:75,  DOI: 10.1186/s12872-015-0070-9. PMID: 26197999